Stroke is a leading cause of adult disability in the US. Available data suggest that Human Immunodeficiency Virus (HIV) infection is strongly associated with ischemic stroke in a young population (15-44 years of age). However, few data exist that address the mechanism of the risk of HIV-associated stroke. Epidemiological studies suggest that HIV-associated stroke is associated with a risk factor profile that differs from the HIV negative young stroke population in that hypertension, diabetes, hyperlipidemia and smoking are not significant risk factors. A large population-based study has demonstrated an association between antiretroviral therapy and an increased risk of cardio- and cerebrovascular events. One proposed mechanism is that HIV affects autoregulation of cerebral blood flow (CBF) to changes in mean arterial pressure (MAP) which in turn increases the risk of stroke. Alternately, it is possible that highly active antiretroviral therapy (HAART) in addition to successfully treating HIV infection may alter cerebral autoregulation and an increased risk for ischemic stroke. This project will address two specific aspects of these mechanisms in HIV induced stroke risk. Specific Aim 1 will test the hypothesis that HIV seropositive patients have impaired cerebral autoregulation determined by measuring changes in CBF using a continuous arterial spin labeling (CASL) approach and Oxygen Extraction Fraction (OEF) using MRI T2*-weighted echo-planar imaging (EPI) sequences, in response to reductions in MAP. The results will be compared with those in HIV negative controls. Specific Aim 2 will test the hypothesis that, in HIV seropositive individuals, HAART results in impaired cerebral autoregulation of CBF independent of the effect of HIV by measuring changes in CBF and OEF using MRI in response to reductions in MAP. We will test the effects of carefully controlled lowering MAP in a carefully monitored setting on CBF and OEF using MRI technology that is reproducible and sensitive to small changes. We have had extensive experience with these techniques. This approach will allow us to determine the importance of these mechanisms in the human disease and potentially provide the information necessary for designing future treatment and prevention strategies for HIV related strokes in the era of HAART. This proposal brings together accomplished investigators from Vascular Neurology, Neuro-HIV, Infectious Disease and Neuroradiology with expertise in MR technology. Through the use of the unique resources and personnel at University of North Carolina, we have the opportunity to provide answers to important clinical and mechanistic questions in HIV and the risk for stroke.